Evaluation of methoxyflurane (Penthrox ) efficacity for acute traumatic pain relief: a pilot study

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1 A R T Y K U Ł O R Y G I N A L N Y / O R I G I N A L PA P E R Otrzymano/Submitted: Poprawiono/Corrected Zaakceptowano/Accepted: Akademia Medycyny Evaluation of methoxyflurane (Penthrox ) efficacity for acute traumatic pain relief: a pilot study Stanislav Groppa 1, Adrian Belîi 2, Gheorghe Ciobanu 3, Boris Leonte 4, Liviu Vovc 5, Eugen Vâlcu 6 1 RM Academy, Department of Neurology and Neurosurgery, SMPhU Nicolae Testemitanu, Chisinau, Republic of Moldova 2 Department of Anaesthesiology and Intensive Care, SMPhU Nicolae Testemitanu, Chisinau, Republic of Moldova 3 National Scientifical and Practical Center of Emergency Medicine, Chisinau, Republic of Moldova 4 National Emergency Department, Chisinau, Republic of Moldova 5 Emergency Department, Emergency City Hospital, Chisinau, Republic of Moldova 6 Resident-neurologist, Department of Neurology and Neurosurgery, SMPhU Nicolae Testemitanu, Chisinau, Republic of Moldova Summary This prospective, descriptive, non-randomized study included patients and presents results of methoxyflurane s (Penthrox ) analgesic efficiency tests for acute traumatic pain relief. Penthrox reduced intensity of acute pain by 68% (95CI 52-84%) and anxiety by 73% (95CI 63-83%) in comparison with initial values (before inhalation). Clinical efficiency of Penthrox with the aim of acute pain relief had a NNT of 2,5, being comparable with that of morphine (NNT=3,6) and better than that of tramadol (NNT=5,5). Penthrox clinical effects satisfied 70% patients. The side pharmacological effects (good mood, dizziness, drowsiness, nausea, logorrhea), which were observed in 85% patients, had no significant negative impact. Anestezjologia i Ratownictwo 10; 4: Keywords: acute pain, analgesia, methoxyflurane Introduction Effective and safe relief of acute pain is not only an important medical problem. Since 04, pain relief is one of the fundamental human rights [1]. None of available today analgesics has the desired efficiency and is without adverse effects [2]. For example, use of nitrous oxide requires expensive equipment and highly qualified medical staff. Combination opioid/ benzodiazepine requires the presence of peripheral venous access to ensure security, and appropriate dose titration of analgesia or sedation are relatively difficult. Ketamine is associated with long recovery time and propofol with respiratory depression. Intravenous regional analgesia requires the presence of a specialized equipment and specialized potential of expertise [3]. One of the possible solutions to the problem of efficient and secure acute pain relief could be analgesic efficiency testing of some drugs within a new frame of indications, drugs used in the past for general anaesthesia. With the exception of nitrous oxide, methoxyflurane (Penthrox ) is the only volatile analgesic, currently available outside the operating room. For this reason, evaluation of analgesic effectiveness, safety and patient s satisfaction, with specifying the possible indications and determining areas of 99

2 Penthrox s application need to be evaluated in light of new knowledge and perspectives. Therefore, we proposed a pilot-study intended to quantify Penthrox effects in severe acute traumatic pain. Material and methods Design of study This prospective, descriptive, non-randomized pilot study was performed at the National Scientific and Practical Centre for Emergency Medicine. The Ethics Committee of the institution approved the study protocol. Inclusion criteria in the study were: adult ( 18 years) with severe pain ( 50 mm on visual analogue score, VAS) of traumatic origin, who had not previously received another analgesic and who gave informed consent to participate in study. Exclusion criteria were based on the presence of contraindications to methoxyflurane administration, such as, for example, kidney or liver disease, diabetes, coma, hemodynamic instability, or patient s refusal to participate in the study. Methoxyflurane (Penthrox ) administration Methoxyflurane was used by the patient by inhalation through the inhaler Penthrox (Figure 1), after a prior brief training. Inhaler, loaded with 3 ml of methoxyflurane, produces a vapour concentration of 0,1-0,2% (when the dilution orifice is open) or 0,3-0,4% (the dilution orifice is closed). Full pharmacological effect establishes after 8-10 deep inspirations. Score of 5 points (very satisfied, satisfied, indifferent, unsatisfied, very unsatisfied). The following situations were defined as severe adverse events: acrocyanosis, apnoea, stridor, laryngospasm, upper airway obstruction, bronchospasm, unstable haemodynamics, paradoxical reactions, pulmonary aspiration, regurgitation, need to intubate trachea, permanent neurological damage. Data analysis Data were filled in Excel tables, version 07 (Microsoft, USA). Statistical analysis was performed with GraphPad Prism software, version 4.1 (GraphPad Software, San Diego, California, USA). For statistical analysis of parameters with continuous values ANOVA test was used. For the number of persons, included in our study, which generated 4 columns of data, a critical value of test F 3,13 allows to identify significant statistical differences with a probability of 95%. Critical value for F was obtained from standardized statistical tables. In case of obtaining a F 3,13, the magnitude of obtained difference was calculated by applying the Bonferroni s post-test of significanc,, where a p 0,05 was considered significant. Results are presented as mean values. In cases considered as relevant, 95% confidence intervals (95CI) were added. Quantifying clinical effectiveness of Penthrox was reflected by using NNT indicator (number need to treat), which represents the number of patients that must be treated to see the expression of the desired clinical effect of the drug in question. To calculate the NNT, as cut-off value of effective/ineffective the reduction of pain intensity by VAS score 50% from baseline was considered. Results Figure 1. Penthrox inhaler and a 3 ml phial of methoxyflurane Data Acquisition General parameters (age, body weight, height) and study specific parameters were recorded. In this context, VAS was used to assess pain intensity and anxiety degree prior to analgesia, during inhalation, immediately after inhalation was finished and more than 45 minutes from the end of Penthrox s administration. Patient s satisfaction was assessed using Likert The study included patients, 12 men and 8 women, with a mean age of 42,7 (95CI 34,3-51) years, an average body weight of 70,7 (95CI 66,5-74,8) kg and an average height of 170 (95CI ) cm. Causes of acute pain were: upper limb joint dislocation 7 (35%) cases, malleolar fracture 4 (%) cases, painful medical procedures 4 (%) cases, transportation of the traumatized patient within the hospital 3 (15%) cases, acute lowerback pain 2 (10%) cases. The analgesic effect obtained by self-administered Penthrox is presented in Figure 2. An average reduction of 68% (52-84% 95CI) of pain intensity from baseline (before inhalation of Penthrox ) was found.

3 VAS, mm Figure 2. Before inhalation Inhalation Postinhalation After 45 min. The analgesic effect of methoxyflurane for acute pain relief VAS, mm Figure 3. Before inhalationinhalation Postinhalation After 45 min. Anxiolytic effect of methoxyflurane for acute traumatic pain relief Decreased pain intensity according to the stages of data acquisition and statistical significance of this phenomenon were reproduced in terms of Bonferroni s post-test in Table 1. The anxiolytic effect obtained by self-administered methoxyflurane is shown in Figure 3. Patient s anxiety decreased with 73% (63-83% 95CI) from baseline. The degree of anxiolysis, according to the stages of data acquisition and statistical significance of the effect are reproduced in terms of Bonferroni s posttest in Table 2. Penthrox clinical effectiveness, reflected in terms of NNT indicator, in our study was 2,5. Comparative analysis of data obtained with those found in the Table 1. Magnitude of decrease in pain intensity in case of analgesia with methoxyflurane Columns of values The differences between average values F p 95% CI of the average differences Before inhalation vs. inhalation 31, 0 7,0 <0,001 18,9 43,3 Before inhalation vs postinhalation 47,6 10,7 0,001 35,4 59,8 Before inhalation vs after 45 min. 53,8 12,1 0,001 41,6 66,0 Inhalation vs postinhalation 16,5 3,7 0,01 4,3 28,7 Inhalation vs after 45 min. 22,8 5,1 0,001 10,6 35,0 Postinhalation vs after 45 min. 6,3 1,4 ns -5,93 18,5 Table 2. Anxiolysis obtained under analgesia with methoxyflurane Columns of values The difference between average values F p 95% CI of the average differences Preinhalation vs inhalation 33,6 7,9 <0,001 22,0 45,1 Preinhalation vs postinhalation 43,7 10,2 <0,001 32,0 55,3 Preinhalation vs after 45 min. 45,2 10,6 <0,001 33,6 56,8 Inhalation vs postinhalation 10,1 2,3 ns -1,8 22,0 Inhalation vs after 45 min. 11,7 2,7 ns -0,2 23,6 Postinhalation vs after 45 min. 1,6 0,4 ns -10,3 13,5 Table 3. Comparative analysis of some analgesics with Penthrox clinical effectiveness in terms of NNT Drug The average value of NNT Nr. of studed patients Etoricoxib 180 mg per os Ibuprofen 400 mg per os Ibuprofen 0 mg per os Morphin 10 mg i.m. Paracetamol 0 mg per os Aspirin 600 mg per os Tramadol mg per os Methoxyflurane (Penthrox) 0,2-0,4% 1,4 2,9 3,0 3,4 4,2 4,9 5,5 2,

4 literature [4] for other analgesics is shown in Table 3. Patient satisfaction, expressed by Likert score is shown in Figure 4. Figure 4. Degree of patient s satisfaction regarding clinical effectiveness of methoxyflurane Thus, 70% of patients felt satisfied with Penthrox effectiveness in acute traumatic pain relief. One patient expressed himself as totally unsatisfied because she had nausea during drug inhalation and she requested to change the analgesic. In the second patient, who expressed as being unsatisfied, the analgesic effect of methoxyflurane was not sufficient to relief pain during malleolar fracture reduction, and necessitated administration of an opioid analgesic (fentanyl). No significant changes were observed clinically or statistically among the values of blood pressure, heart rate, respiratory rate and sedation level during or after methoxyflurane inhalation. No severe adverse events, as, mentioned in the above list, were noted. Pharmacological side effects, not necessarily being negative and considered clinically insignificant, were present in 85% of patients: good mood in 14 (70%) patients, dizziness in 13 (65%) patients, drowsiness in 6 (30%) patients, nausea in 1 (5%) patient and logorrhea in 1 (5%) patient. Discussion There are few contemporary publications describing the analgesic effectiveness of Penthrox. Babl F. and co. (06), in a study performed on a group of 105 paediatric patients, reported a 34% reduction of acute pain intensity, treated at pre-hospital stage [5]. Buntine P. and co-authors (07) reported in adult patients 24-32% reduction of the acute pain intensity in the same conditions [6]. Our data (reduction of pain intensity by 68%; 95CI 52-84%) indicate a doubled magnitude of analgesic effect in comparison with the quoted above. These differences could be probably explained by socio-cultural differences between Australian and Republic of Moldova s population, also by using Penthrox in other indications than those, which were compared with data or by comparatively small number of patients included in our study. Index NNT of 2,5 places methoxyflurane at the level of morphine (NNT 3,4), far outmatching tramadol (NNT 5,5) the only comparable drugs, for the acute traumatic pain relief. Observed in our study more gradual pattern of analgesic in comparison with the anxiolytic effect can be explained by the fact that the start of medical procedures inhibits the phenomenon of events anticipating, produced by cortex and, respectively, the degree of anxiety. To the contrary, nociceptive influx, augmented by medical procedures, counterbalances the analgesic effect of the drug, reached highest level after the surgery. Satisfaction rate of 70% in our study is comparable to that reported in a meta-analysis of Grindlay and Babl (09) 94% of patients and 74% of nurses were satisfied with the effect [7]. Although the nephrotoxic effect of methoxyflurane was not part of our research, this aspect was almost always mentioned by the doctors who took care of patients in our study. After a break of about 30 years, when it was removed from the arsenal of anaesthesia because of its nephrotoxic effect, methoxyflurane (Penthrox ) gets back on the global market as an analgesic for acute pain relief. Short durations of administration and significantly lower doses of methoxyflurane (Penthrox ), required to relief pain, avoid nephrotoxic effect, which is dependent on the dose and duration of exposure. To produce a subclinical nephrotoxic effect in adult patient requires a dose of -24 g (96 ml) of methoxyflurane in comparison to maximal dose for 24 hours of 1,5g (6 ml), recommended and used today [7]. Conclusions 1. Penthrox reduced acute pain intensity by 68% (52-84%; 95CI) from baseline (before inhalation). 2. Penthrox reduced anxiety by 73% (63-83%; 95CI) from baseline (before inhalation). 3. Clinical effectiveness of Penthrox for acute pain relief is comparable to that of morphine and better 102

5 than that of tramadol (NNT respectively 2,5 vs. 3,4 vs. 5,5), achieving a patient s satisfaction level of 70 %. 4. Pharmacological side effects (good mood, dizziness, drowsiness, nausea, and logorrhea), recorded in 85% of patients, had no significant negative impact. Correspondence address: Adrian Belîi Department of Anaesthesia and Intensive Care City Emergency Hospital, 1, Toma Ciorba street, MD 04 Chisinau, Republic of Moldova Phone: adrian_belai@hotmail.com Piśmiennictwo 1. Brennan F, Carr D, Cousins M. Pain management a fundamental human right. Anesth Analg 07;105: Krauss B, Green S. Procedural sedation and analgesia in children. Lancet 06; Davidson A, Eyres R, Cole W. A comparaison of prilocaine and lidocaine for intravenous regional anaesthesia for forearm reduction in children. Paediatr Anaesth 02;12: Melzack R, Wall P. Textbook of Pain. Churchill Livingstone Editions. 5-th edition, section 3; 05. p Babl F, Jamison S, Spicer M, Bernard S. Inhaled methoxyflurane as a prehospital analgesic in children. Emerg Med Australas 06;18: Buntine P, Thom O, Babl F, Bailey M, Bernard S. Prehospital analgesia in adults using inhaled methoxyflurane. Emerg Med Australas 07;19: Grindlay J, Babl E. Review article: Efficacy and safety of methoxyflurane analgesia in the emergency department and prehospital setting. Emerg Med Australas 09; 21: